IE882286L - Oral sustrained release acetaminophen formulation and process - Google Patents
Oral sustrained release acetaminophen formulation and processInfo
- Publication number
- IE882286L IE882286L IE882286A IE228688A IE882286L IE 882286 L IE882286 L IE 882286L IE 882286 A IE882286 A IE 882286A IE 228688 A IE228688 A IE 228688A IE 882286 L IE882286 L IE 882286L
- Authority
- IE
- Ireland
- Prior art keywords
- acetaminophen
- tablet
- sustained release
- weight
- release layer
- Prior art date
Links
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 title claims abstract description 223
- 229960005489 paracetamol Drugs 0.000 title claims abstract description 104
- 239000000203 mixture Substances 0.000 title claims description 52
- 238000000034 method Methods 0.000 title claims description 19
- 238000009472 formulation Methods 0.000 title description 3
- 239000003826 tablet Substances 0.000 claims abstract description 111
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 43
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 43
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 42
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 33
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims abstract description 31
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims abstract description 31
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 29
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 29
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 29
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims abstract description 27
- 229940069328 povidone Drugs 0.000 claims abstract description 25
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 24
- 238000005469 granulation Methods 0.000 claims abstract description 23
- 230000003179 granulation Effects 0.000 claims abstract description 23
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 21
- 229920000881 Modified starch Polymers 0.000 claims abstract description 17
- 230000003628 erosive effect Effects 0.000 claims abstract description 16
- 239000000314 lubricant Substances 0.000 claims abstract description 14
- 238000002156 mixing Methods 0.000 claims abstract description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000005550 wet granulation Methods 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims abstract description 8
- 239000007939 sustained release tablet Substances 0.000 claims abstract description 7
- 238000003801 milling Methods 0.000 claims abstract description 6
- 239000012730 sustained-release form Substances 0.000 claims description 62
- 238000013268 sustained release Methods 0.000 claims description 61
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 42
- 239000004615 ingredient Substances 0.000 claims description 38
- 239000003979 granulating agent Substances 0.000 claims description 31
- 239000011159 matrix material Substances 0.000 claims description 31
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 29
- 229920002472 Starch Polymers 0.000 claims description 20
- 239000008107 starch Substances 0.000 claims description 20
- 229940032147 starch Drugs 0.000 claims description 20
- 235000019698 starch Nutrition 0.000 claims description 20
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 17
- 239000001913 cellulose Substances 0.000 claims description 16
- 239000000843 powder Substances 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 229920003124 powdered cellulose Polymers 0.000 claims description 7
- 235000019814 powdered cellulose Nutrition 0.000 claims description 7
- 230000002459 sustained effect Effects 0.000 claims description 7
- 230000001225 therapeutic effect Effects 0.000 claims description 7
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 6
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 5
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 5
- 235000021355 Stearic acid Nutrition 0.000 claims description 4
- 239000007891 compressed tablet Substances 0.000 claims description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 4
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 4
- 239000008117 stearic acid Substances 0.000 claims description 4
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229940100486 rice starch Drugs 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- 235000019441 ethanol Nutrition 0.000 claims 2
- 229920002785 Croscarmellose sodium Polymers 0.000 claims 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 1
- 229960001681 croscarmellose sodium Drugs 0.000 claims 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims 1
- 229910052710 silicon Inorganic materials 0.000 claims 1
- 239000010703 silicon Substances 0.000 claims 1
- 229920003109 sodium starch glycolate Polymers 0.000 claims 1
- 229940079832 sodium starch glycolate Drugs 0.000 claims 1
- 239000008109 sodium starch glycolate Substances 0.000 claims 1
- 239000012530 fluid Substances 0.000 abstract description 6
- 239000000377 silicon dioxide Substances 0.000 abstract description 2
- 235000012239 silicon dioxide Nutrition 0.000 abstract description 2
- 239000010410 layer Substances 0.000 description 53
- 208000029618 autoimmune pulmonary alveolar proteinosis Diseases 0.000 description 15
- 239000011230 binding agent Substances 0.000 description 12
- 239000007894 caplet Substances 0.000 description 9
- 235000010980 cellulose Nutrition 0.000 description 9
- 229920002678 cellulose Polymers 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 239000008213 purified water Substances 0.000 description 7
- 239000002775 capsule Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 229920003072 Plasdone™ povidone Polymers 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 230000036470 plasma concentration Effects 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 3
- 241000206607 Porphyra umbilicalis Species 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 244000061456 Solanum tuberosum Species 0.000 description 2
- 235000002595 Solanum tuberosum Nutrition 0.000 description 2
- 241000209140 Triticum Species 0.000 description 2
- 235000021307 Triticum Nutrition 0.000 description 2
- 240000008042 Zea mays Species 0.000 description 2
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- -1 alkali metal carboxymethvl Chemical class 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- RCUDFXMNPQNBDU-VOTSOKGWSA-N cinepazide Chemical compound COC1=C(OC)C(OC)=CC(\C=C\C(=O)N2CCN(CC(=O)N3CCCC3)CC2)=C1 RCUDFXMNPQNBDU-VOTSOKGWSA-N 0.000 description 2
- 235000005822 corn Nutrition 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 239000007942 layered tablet Substances 0.000 description 2
- 229910052751 metal Chemical class 0.000 description 2
- 239000002184 metal Chemical class 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920003075 Plasdone™ K-29/32 polymer Polymers 0.000 description 1
- 240000006394 Sorghum bicolor Species 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000037058 blood plasma level Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 229920006184 cellulose methylcellulose Polymers 0.000 description 1
- 229960004201 cinepazide Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- IOVGROKTTNBUGK-SJCJKPOMSA-N ritodrine Chemical compound N([C@@H](C)[C@H](O)C=1C=CC(O)=CC=1)CCC1=CC=C(O)C=C1 IOVGROKTTNBUGK-SJCJKPOMSA-N 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
An acetaminophen-sustained release tablet or tablet layer is formed by making a wet granulation, using Povidone (PVP) in water or alcohol-water as the granulating fluid which is mixed with acetaminophen, hydroxyethyl cellulose, a wicking agent e.g. microcrystalline cellulose, then drying and milling the granulation and blending with dry powdered erosion promoter, e.g. pregelatinized starch, wicking agent, lubricant e.g. magnesium stearate and glidant e.g. silicon dioxide, and compressing the resultant granulation, which upon administration results in a slow release of the acetaminophen.
[EP0305051A1]
Description
£ 9 ~ 7 1 This invention relates to a sustained release form of acetaminophen, and is more particularly concerned with an acetaminophen-containing matrix formed, from granulations-of acetaminophen mixed with inactive powdered excipients plus hydroxyethyl cellulose (HEC) using an aqueous solution of Povidone U.S.P. (polyvinylpyrrolidone - FVP) as the granulating agent, which granulations are dried, milled, blended with additional inactive powdered e'xcipients, and then compressed into a tablet,, and to the p.r'ocess of making the acetaminophen-containing matrix in a manner so that the rate of release of acetaminophen can. be varied or controlled.
Background off Present Invention.
Acetaminophen (APAP) is a well-known analgesic and antipyretic drug. In the United States, it is available for non-prescription over-the-counter sale in conventional liquid, suppository, capsule, tablet and caplet dosage forms. The tablet and! caplet dosage forms typically contain 325 mg acetaminophen as "regular strength" or 500 mg as "extra strength". Normally, regular strength tablets or caplets are taken as one or two every four hours, and the extra strength tablets or caplets are taken as one or two every six hours. Ideally, it would be desirable to extend the dosing interval while maintaining the initial plasma concentrations achievable with conventional tablets or caplets. This would provide immediate and extended therapeutic analgesic or antipyretic effect and reduce the number of doses necessary, thereby making therapy more convenient. A way to do this has now been found, using the present 2 invention, whereby' two tablets or caplets each containing 650 mg acetaminophen can be formulated to provide both immediate release and sustained release or sustained release alone such that the dosing interval can be 5 extended to at least eight (8) hours. In addition, the quantity (amount) of the sustained release matrix can be adjusted up or down to produce tablets for sustained release that have more or less than 650 mg of acetaminophen. For example, a tablet containing 500 mg of 10 acetaminophen can be manufactured from the same ' • ' composition by simply decreasing the sis© and weight of the final tablet by a multiple of 10/13. The present invention can be used to obtain any desired sustained release acetaminophen tablets of different dosages, e.g. a 15 500 mg sustained release tablet which results in lower blood plasma levels over eight hours, than with the 650 mg tablet,, and desired longer or shorter time periods,, e.g. twelve hours are possible. From a practical standpoint eight (8) hours might be the most desired interval,, The 20 matrix of the present invention can be used to make acetaminophen sustained release pharmaceutical . preparations in compressed tablet form. The matrix materials used are compressed into a shaped tablet form. The term "tablet" as used herein includes tablets of any 25 shape,, and includes caplets, which ere tablets having a capsule shape. The tablets may be coated with a pharmaceutical^ acceptable coating material or have pharmaceutical^ acceptable coloring added to the composition prior to compression. 30 Prior Art Both hydroxyethyl cellulose (HEC) and polyvinyl pyrrolidone (PVP) have been used in pharmaceutical 35 compositions, such as tablets, including sustained release 3 compositions. However, the materials have not been used in the same way for the same purposes in a sustained release acetaminophen tablet composition. In U.S. 4189469 the examples show pharmaceutical compositions containing a 5 xanthine as the active ingredient together with hydroxyethyl cellulose, PVP# and certain excipients. However, no wicking agent or erosion promoting agent is used there, so that the method of obtaining the sustained release effect is different in Applicant's invention. The ratio of drug to 10 hydroxyethyl cellulose used is much higher in Applicant's., sustained release formulations. Also, the reference does not refer to the use of wet granulation techniques which are required in Applicant's invention. 15_ U.S. 4264573 teaches the use of PVP but does not teach the « use of hydroxyethyl cellulose. It is typical of the many formulations for slow release via controlled surface erosion which are known in the prior art.
US-A-4097606 relates to APAP tablets having an improved absorption rate (faster onset of pharmacological action) compared to conventional APAP tablets. The tablets of US-A-4097606 contain from 190 to 1000 mg of APAP, 30 to 90 mg of an alkali metal carboxymethvl starch and a binder, the ratio of APAP to carboxymethyl starch being from 5:1 to 10:1 by weight and the quantity of binder not exceeding that of APAP, Additionally the tablets optionally contain polyvinylpyrrolidone (povidone) a disintegrant such as corn starch or potato starch, a lubricant such as magnesium stearate„ talc or stearic acid, a diluent such as lactose or sucrose, and a flow aid such as colloidal silicon dioxide. The binder may be microcrystalline cellulose.
EP-A-0130683 concerns a free-flowing particulate APAP 35 composition capable of being directly formed into a tablet having high hardness, a short disintegration time and a short dissolution time. The particulate composition comprises APAP, a partially gelatinized starch, a lubricant 20 25 30 4 and water. The lubricant may ba, for example, stearic acid or a metal salt thereof. Optionally, the composition contains a binder, such as starch paste (fully gelatinized starch) , pregelatinized starch (a fully gelatinized starch) , 5 polyvinylpyrrolidone or other such materials. Another optional component is a disintegrant, for example corn starch or another non-gelatinised starch, sodium carhoxvmethyl starch (sodium starch glvcolate), microcrystalline cellulose or cross-linked polyvinyl-10 pyrrolidone.
FR-A-2588188 relates to a sustained release composition for oral administration of a water soluble salt of cinepazide. The composition comprises a cinepazide salt; a hydrophilic 15 cellulose polymer selected from hydroxymethyl cellulose, hvdroxyethyl cellulose,, hydroxypropylcellulose and hydroxypropylmethyl cellulose; polyvinylpyrrolidone; and a lubricating agent which is magnesium stearate, hydrogenated castor oil or a mixture thereof. The tablet does not 20 require other components.
US-A-46S1521 is concerned with a free flowing, particulate APAP composition capable of being directly formed into a tablet having high hardness, a short disintegration time and 25 a short dissolution time. The composition contains from 84 to 94 wt« % APAP, 5 to 15 wt. % pregelatinized starch,, a lubricant (e.g. stearic acid or a metal salt thereof) and water. Optionally, the composition contains an additional binder, such as starch paste, polyvinylpyrrolidone, 30 hydroxypropyl cellulose or hydroxypropylmethyl cellulose, for example.
GB-A-1390032 and FR-A-2150903 relate to free-flowing granular materials containing APAP and suitable for 35 tabletting. According to these two specifications, the bulk volume of APAP in tablets is close to the acceptable limit for tablets, and the specifications address the problem of minimising additions of other substances to APAP tablets. 5 The material contains more than 80 wt. % APAP and from 1.5 to 10 wt. % of a water-soluble polymeric organic binder-The binder may be polyvinylpyrrolidone or a cellulose derivative such as hydroxvethyl cellulose, hydroxypropv1 5 cellulose or sodium carboxymethyl cellulose, for example. The material optionally contains up to 7% toy weight of the APAP of a starch (e.g. corn starch) or a derivative thereof.
Summary of the Invention • 10 The present invention, in its process aspect is directed to the process of preparing an acetaminophen-sustained release shaped and compressed tablet characterised by a slow release of the acetaminophen upon administration comprising the 15 following steps: A) forming a granulating agent by dissolving 5-25 parts by weight povidone in water or in an alcohol-water mixture; 20 B) blending together the following parts by weight of the total composition of ingredients with sufficient acetaminophen so. that the acetaminophen comprises 68 to 94. percent by weight of the total composition in dry powder form; 6 ingredient Parts by Wgiqht Hydroxyethyl Cellulose 5-25 wicking agent 5-25 5 e.g. Microcrystalline Cellulose C) adding the granulating agent from Step A to the' blended powders from Step B, and mixing in a high io shear granulator to form a wet granulation; D) drying the wet granulation of Step C; E) milling the dried granulation from Step D; 15 20 30 F) thoroughly blending the milled dried granulation from Step E with the following ingredients in dry powder form; Inaredient Parts bv Weight erosion promoter e.g. 1-15 Pregelatinized Starch wicking agent e.g. 5-45 25 Microcrystalline Cellulose lubricant e.g. 0-10 Magnesium Stearate glidant e.g. Colloidal 0-5 Silicon Dioxide G) compressing the final granulation from Step F into a tablet or tablet layer.
In its product aspect the present invention is directed to 35 a shaped and compressed sustained release therapeutic i composition comprising acetaminophen as the therapeuticalIv-active medicament, a granulating agent and excipients combined into a matrix, characterized by a slow release of the acetaminophen medicament upon administration, wherein 5 the granulating agent and excipients include hvdroxyethy 1 cellulose, povidone, a wicking agent and an erosion promoter, and wherein the total amount of ingredients other than acetaminophen in the sustained release matrix is effective to bind the acetaminophen in a sustained release 10 solid matrix but is less than 32 percent, preferably less than 15 percent, of the weight of said shaped and compressed composition , the composition being made by the process defined above and in claim 1.
The preferred tablets of this invention include a shaped and 15 compressed acetaminophen sustained release tablet made by wet granulating a sufficient amount of acetaminophen to comprise from 68 to 94 weight percent of the total composition with the excipients of Part I with the Granulating Agent of Part II, drying and milling the 20 resultant granulations, and then blending with the Excipients of Part III and compressing into a tablet, wherein the ingredients of Parts I, II and III comprise the following; Ingredient Parts bv Weight 25 Part I Excipients Hydroxyethvl Cellulose 5-25 Microcrystalline Cellulose 5-25 30 Part II Granulating Agent Povidone 5-25 Water or Alcohol-Water q.s Part III Excioients 35 Pregelatinized Starch 2-15 Microcrystalline Cellulose 5-43 Magnesium Stearate 0-10 Colloidal Silicon Dioxide 0-5 8 The invention preferably is utilized in the form of a bi-layer tablet containing both an immediate release layer and a sustained release layer- Accordingly, the invention includes a process of preparing aw acetaminophen sustained release bi-layer tablet comprising a first layer of immediate release and a second layer of sustained slov release of acetaminophen according to the steps of: X) preparing an immediate release layer comprising . acetaminophen and pharmaceutic®lly acceptable . excipients; II) preparing a sustained! release layer comprising acetaminophen as the active ingredient according to Steps A to ? of claim 1; and III) combining and compressing the inunediate release layer of Step I with the sustained release layer of Step II into a bi-layered tablet.
In another aspectt there is provided a shaped and compressed hi-l&yer therapeutic composition comprising acetaminophen in a first immediate release layer and in a second sustained release layer, wherein the immediate release layer comprises acetaminophen and pharmaceutical^ acceptable excipients and the sustained release layer comprises the composition according to claim 6» A further aspect of the invention resides in a shaped and compressed bi-layered immediate release layer and sustained release layer acetaminophen tablet made by combining an immediate release layer comprising acetaminophen and pharmaceutical^ acceptable excipients with a composition according to claim 9. t) In addition to the hydroxyethyl cellulose and PVP polyiners discussed above which are "Matrix Binding Agents", the commonly used excipients which are granulated with -the acetaminophen must include a "wicking agent" (to wick fluids 5 "Into the matrix) such as microcrystalline cellulose, and ah "'erosion promoter9* such as pregelatinized starch. Additional excipients which are added to the granulated asnsd dried ingredients include a - wicking agent such as microcrysta 11 ine cellulose, an erosion promoter such as 10 pregelatinized starchy and optionally a lubricant such as magnesium stearate and a glidant such as colloidal silicon -dioxide. The use of a lubricant is preferred, while the use of a glidant is possible but not usually needed.
Detailed Description of the Invent ion 15 20 The acetaminophen sustained! release isatrix charmaceirt-S.pai tablets of the present invention are made by adding granulating agent to a. drv ponder blend of active drug and inactive excipients to fonawet granulations, which are then dried and finely divided, e.g, by milling the dried! granulations into a finer powder foma, then blending with additional inactive powdered excipients and ocnoressinq 10 into tablets. Tablets can be readily manufactured using conventional tabletting equipment. ' The tablets of the present invention have novel and 5 advantageous features. A primary advantage is that the tablets are bioerodible when swallowed, that is, no insoluble tablet shaped device remains to be excreted or removed from the body after acetaminophen is depleted from the tablet. The acetaminophen sustained release matrix ,10 uses hydroxyethyl cellulose (Hydroxyethyl Cellulose NF) and povidone (Povidone USP) (Plasdone® K29/32) (PVP) as the Matrix Binding Agents for obtaining the sustained release effect. This combination of two well-known pharmaceutical^ acceptable polymers, in the relative 15 proportions here used and in the manner used is believed. to be a major novel feature of the present invention. In the most preferred embodiments of the invention, the amount of hydroxyethyl cellulose used is on the general order of four percent or less of the amount of 20 acetaminophen, while the amount of povidone is on the general order of four percent or less of the amount o£ acetaminophen used. This means the acetaminophen sustained release matrix of the present invention is capable of producing dosage forms having very high 25 drug/matrix binding agent ratios. This results in reducing the size or number of tablets needed, making the product easier to swallow, less expensive and more desirable to the consumer. 30 Another advantage of this invention is that the rat© of matrix erosion when the tablet is swallowed can be modified so that the degree and/or length of the sustained release effect of the matrix can be easily modified by simply altering the levels of the other excipients, aside 35 from the hydroxyethyl cellulose and the povidone (PVP). 11 Hence, the rate at which acetaminophen is released from the tablet and subsequent absorption from the gut into the bloodstream can be modified to match the desired blood pla srr.a concentration versus time profile. 5 The acetaminophen sustained release matrix of the present invention can be used alone as a shaped and compressed, tablet (tablet can be any shape such as oval., round, caplet or spherical), or as part of a multi-layered tablet 10 containing an immediate or quick-release layer to elevate • - - the"'blood levels of acetaminophen quickly e;nd also containing a sustained release portion to maintain the elevated blood level- Hence, the present invention can be used to prepare tablets with two or more layers, each with 15 a significantly different release rate of the same component, or to prepare tablets of different-components where a combination of drugs is desired.
The acetaminophen sustained release matrix, in our 20 currently preferred embodiments, contains approximately three percent hydroxyethyl cellulose and approximately three percent povidone (PVP), with the balance consisting of various pharmaceutically acceptable, common excipients. The matrix tablets or tablet layers of the 2 b present invention have a very high drug-to-excipients ratio on the order of 85 percent acetaminophen to 15 percent excipients by weight. This results in a drug to total matrix weight ratio of apprcsdirately Is 1.2. 30 As discussed, the hydroxyethyl cellulose and PVP polymers are Matrix Binding Agents„ The additional commonly used excipients that are granulated with the acetaminophen include a Wicking Agent (to wick fluids into the matris) such as microcrystalline cellulose. Additional excipients 35 that are added to the granulated and dried ingredients 12 include a wicking agent such as microcrystalline cellulose, an Erosion Promoter such as pregelatinized starch, and a lubricant such as magnesium stearate. 5 For each of the ingredients used in the sustained release matrix of the present invention,, aside from the acetaminophen, the hydroxyethyl cellulose,, and the povidone (PVP) there exists less preferred alternative or equivalent materials which could be used in its place. 10 The"' foUowing''Table J lists each of the various pref@Kr.ed ingredients, the purpose of the ingredient, the preferred weight of such preferred ingredient, the usable weight range of the preferred ingredient,, other less preferred alternatives or equivalents which can be substituted for 15 the preferred ingredient, the preferred weight of such' alternate ingredient and the usable weight range of such alternate ingredient needed for a sustained release layer containing 325 mg of acetaminophen. For matrices (tablets or caplets) of a higher or lower level of acetaminophen, 20 the amounts of ingredients and their ranges would be proportionately increased or decreased.
The ingredients are listed in Table I under Part I Active h Excipients, Part II Granulating Agent, Part III 25 Excipients, sine© they are used in this manner in the process by which the tablets of the present invention are made.
The preferred process which is utilised to form the most 30 preferred acetaminophen sustained release matris of the present invention is to mis together the dry powdered active drug, acetaminophen, the dry powdered matrix binding agent, hydroxyethyl cellulose, and the dry powdered wicking agent, microcrystalline cellulose in a 35 mixer/granulator. A granulating fluid or solution is 13 formed by dissolving povidone into water at a ratio of 19.1 grams of povidone to 100 grams of -water. The resultant granulating agent is sprayed onto the above admixed powders while they are being mixed in the 5 mixer/granulator so as to form a wet granulation. The -wet granulation thus obtained is dried and milled.. At this point, a small amount of dry powdered excipients such as pregelatinized starch, microcrystalline cellulose and magnesium stearate are added, and mixed with the milled 10 "granulations, after which theyare.compressed thereby forming the sustained release matrix.
TABLE I SUSTAINED RE&EASE ACETAMIHOPHEH MATRI3 Preferred Ingredient Purpose (mg) Wt.per Tablet (mg) Alts or Range Equlv- (mg) ■ (mg) Wt.per "■ tablet mmm. 10 Part 1 - Achive & Excipients Acetaminophen, USP .
Hydroxyethyl Cellulose NF (Natrosol*/250L) Active Matrix Binding Agent 325 10.7 5-25 jsuias»S Microcrystalline Cellulose NF, (Avicel* Wicking PH 101,102,103 r105) Agent 10,7 Powdered Cellulose 5-25 (Solka Floe*') 10.7 5-25 Part II - Granulating Agent 15 Povidone, USP Matrix (Plasdone* K29/32) Binding i. Agent Purified Water, USP Solvent 10,7 5-25 q.s water-alcohol (up to 50%) Preferred Ingredient: Purpose (mg) Wt.per Tablet Part 111 - Excipients 5 Microcrystalline Cellulose USP(Avicel* Wicking PH 101,103,103,105) Agent 15,0 Pregelatinized Erosion 5.0 Starch, NF Promoter 10 (corn, wheat, or potato source) 20 25 Magnesium Stearale NF Lubricant '5.0' (mg) Alt. (mg) (mg) or Wt.pe Range Eauiv. -Tablet Range Pondered Cellulose 5-4 5 CSplka Floe8) 15.0 5-4 5 2-15 Starch NF 5.0 5-10 (corn/ . wheat or potato) or rice starch, Sod i urn 3.0 1-10' .Starch ! Glycolate HF(Explotab*) Croscarmellqse 3.0 1-10 Sodiura NF (Ac Di Sol*) Crospovidone 3.0 1-10 NF{PoYidone*XL) 0-10 Stearic Arid NF 5.0 5-10 16 Example I Acetaminophen Sustained Release Bi-Laver Tablet This example illustrates a bi-layer tablet in which there 5 is both an immediate release layer and a sustained release layer. The immediate release layer is analogous in composition and manufacturing procedure to currently available over-the-counter acetaminophen non-sustained release tablets. It is the sustained release layer that 10 utilises the matrix of the present invention. The acetaminophen content of the entire tablet is 650mg„ The bi-layer tablet uses the following ingredients: 15 Ingredient. mg/Tablet A. Immediate Release Laver Part I - Active and Excipients 20 Acetaminophen, USP 325.0 mg Powdered Cellulose, NF 42.3 mg Pre-gelatinized Starch, NF 16.0 mg Part Ii - Granulating Aoent 25 Starch, NF 26.0 mg Purified Water USP q.s.
Part III - Excipients Sodium Lauryl Sulphate, NF 0.75 mg 30 Magnesium Stearate, NF 2,0 ma Total 412.05 mg I / B. Sustained Release Laye? ma/Tablet 10 Acetaminophen, USP Hydroxyethyl Cellulose, NF (Natro'sol* 25QL) Microcrystalline Cellulose,, NF (Avicel* PH 101) 325.0 mg 10.7 mg 10.7 mg 15 P a ihj^ Granulating Agent Povidone# USP (Plasdone* X29/32) Purified Mater* USP 10.7 mg q.s Microcrystalline Cellulose, USP (Avicel* PH 101) 20 Pregelatinized Starchy NF (Starch 1500)* Magnesium Stearate, NF Total 15-0 mg 5.0 mg .. P.. im 25 Total Tablet Weight 794.13 mg The above ingredients are utilized to make a bi-layer -tablet# by the following working directions:. 30 Working Directions immediate Release Laves 35 1. Weigh the components of Part I and add them to the bowl of a fluid bed granulator (Aeoromatic). 2. Prepar? the granulating agent (Part XI) by adding the Purified Water to a processing tank (approximately 15 grams water for each gram of Starch NF)■ Slowly mix in the starch and heat the mixture until the temperature reaches 82°C-84°C. ■ 3. With the components of Part I in a bested fluidized state (inlet air temperature 75®C to 859G),, spray the granulating -"agent onto the powders. 4. After all the granulating agent has been sprayed,, dry the granulated powders to a moisture content of 1.4-1.9% as determined by loss on drying (e.g. Computrac). 5. Sieve the dried granulation (e.g. Glatt Quick Sieve: Stator No. 3, Screen No., 1.5mm, 1000 RPM). Other machines such as Fitzpatrick Communition Mill can be used. 6. Blend the sieved and dried granulation with the powders of Part III using a suitable mixer such as a twin-shell, ribbon or planetary miser.
B. Sustained Release Layer 1. Weigh the components of Part I and preblend in a high shear miser (Fielder: impeller speed of approximately 250 HPM for 1 minute). 2. prepare the.granulating agent (Part II) by dissolving the Povidone USP in the Purified Mater USP (a ratio of 19.1 grams of povidone to.100 am of water). 3. Spray the granulating agent at a rate of 400 ml/min onto Part I in the high shear mixer. Granulate the 19 mixture for one minute after the addition of Part 11 (Fielder; impeller speed of approximately 3000 RPM). 4. Remove the completed wet granulation from the 5 high shear mixer and load it into the product bowl of a fluid bed apparatus (e.g. Aeromatic or Glatt). With an. inlet air temperature of approximately 609C, dry the . granulation to a moisture level of 2.0 to 2.5% as ■" - determined by loss on drying (e.g. Computrac). The wet 10 granulation can also be dried on trays in drying ovens. 5. . Sieve the dried granulation (Glatt Quick Sieve: 1.5mm Screen, Stater No. 3# 395 RPM). Other machines such as a Pitzpatriek Communition Mill can be used. • 15 6. Blend the sieved and dried granulation with the powders of Part III using a suitable miser such as a twin-shell# ribbon or planetary mixer. 20 C. Compression of Tablets or Caolets 1. Load the granulation of the immediate release layer into one hopper and the granulation of the sustained release layer into the second hopper of a bi-layer 25 tableting machine (e.g. Stokes Versapress). Compress tablets using 0.749 x 0.281 x 0.060 extra deep concave capsule shaped tooling (Tablet Tooling of other shapes such as oval or round can also'be used). The sustained release layer has a target weight of 382.1 mg and the 30 immediate release layer lias a target weight of 412.05 mg. Ideal- tablet hardness immediately after compression is 7-12 Kp. 35 The bi-layer tablets of Example I were tested in twelve adult male human subjects and compared to non-sustained 20 release (immediate release only) tablets in a cross-over design. Two tablets of Example I, which contained 1300 mg of acetaminophen, were dosed at time * 0 hour. The non-sustained release tablets, each containing 500 mg 5 acetaminophen «ere dosed as tv^o tablets (1000 mg acetaminophen) also at time « o hour,. Subjects were fasted at least 8 hours prior to administration of the dose. Blood samples were taken from each subject at 0, 1, ... • 1.5, 2, '3, 4, 6, 8# 10 and 12 hours. Plasma.was separated 10" from the 'blood and the concentration of 'acetaminophen-'in each sample was determined. The results are shown numerically in Tables 2a and 2b. The results -show that two bi-layer tablets of Example I, when compared to two tablets of non-sustained release•acetaminophen (1000 mg 1,5 dose), achieve the following; comparable rate of absorption? comparable maximum plasma concentration; and comparable extent of absorption (AUG or area under the curve) when adjusted for dose. Theoretically, the 1300 mg dose should provide 130% of the AUC of the 1000 mg dose, 20 The results from Tables 2a and 2b show comparable extents of absorption by the following calculation: (64.3 •; pg. (meg)/ml divided by 49.5-.jjg' (meg)/ml) x 100% = i-30%.
The tablets of Example I provide the opportunity to dose 25 30% more acetaminophen in a more convenient manner by ' extending the dosing interval to at least eight hours.
TABLE 2a Sustained Release Acetaminophen 650 rag bi-layer tablets. (Example I) Average Plasma Concentration Levels of 5 Acetaminophen (|j,g/ml) in twelve subjects after administration of two tablets (1300mg>. Average AUG equaled 64.3' ng./h.
TIME (HOURS); POST DOS IMG 10 0 1.0 1-5 2.0 3.0 4.0 6.0 8.0 10.0 12.0 Average (u.g/ml) 15 0 12.5 12.8 11.9 10.0 7.S 4.4 2..5 1.6 1.0 TABLE 2b Non-sustained Release Acetaminophen 500 rag tablets. 20 Average Plasma Concentration Levels of Acetaminophen (ug/ml) ; in twelve subject. Average AUG equaled 49.5 ji-g/h.
TIME (HOURS) POST DOSING 25 0 1.0 1.5 2.0 3.0 4.0 6.0 8.0 10.0 12.0 Average (ug/ml) 0 12.1 11.4 10.0 7.3 5.3 2.9 1.8 1.1 0,6 30 22 Acetaminophen Sustained Release Tablet Containing 650 ma of Acetaminophen in Matrix Form 5 This example illustrates an all-matrix (mono-layer) tablet in which there is only a sustained release layer.. The working directions are analogous to the working directions for the sustained release layer described in Esample I except that the amounts ofi all ingredients ar© 10 proportionally increased such that the final tablet contains 650 mg acetaminophen. Tablets can be compressed using capsule,, oval, round or other- appropriately shaped ' tooling. The final target weight of the compressed tablet is 764.2 mg.
IS Ingredient mq/Tablet Part I - Active and Ercioients Acetaminophen, USP 650.0 rag Hydroxyethyl Cellulose,. NF 21.4 rag (Natrosol*) 250L) 20 Microcrystalline Cellulose, NF 21.4 mg (Avicel® PH 101) Part II - Granulating Agent Povidone, USP 21.4 mg 25 (Plasdone* K29/32) Purified. Water, USP q.s Pa : Microcrystalline Cellulose, NF 30.0 sag 30 (Avicel* PH 101) Pregelatinized Starch, NF -10.0 mg (Starch 1500*) Magnesium Stearate, HF 10-0 mg 35 Total 764.2 mg 23 Example III Acetaminophen Sustained Release Bi-layer Tablet Containing More than a total of 650 mo acetaminophen This example illustrates a bi-layer tablet which is analogous to" the tablet described in Example I, except all amounts of ingredients per tablet and final weight of the tablet are proportionally increased. The amount of the increase is theoretically indefinite, but one practical amount would be a 16 2/3 mg increase in the amount of acetaminophen such that the total amount of acetaminophen in a tablet would be 666 2/3 mg- . Hence,, if the tablets were dosed as two every eight hours, the maximum total amount of acetaminophen consumed in a 24 hours period would be 4 grams. The working directions for the < immediate release layer and the sustained release layer are analogous to the working-directions described, ia Example I. Tablets can be compressed using capsule, oval, round or other appropriately shaped tooling. For a tablet containing a total of 666.66 mg (an approximation of 666 2/3 mg) acetaminophen, the sustained release layer has a target weight of 391.99 mg and the immediate release layer has a target weight of 422.65 rag.
Ingredient mgZXahlsk A. Immediate Release Layer Part I - Active and Excipients Acetaminophen,, USP Powdered Cellulose, NF Pregelatinized Starch, NF 333.33 mg 43.4 mg 16.4 mg 24 Ingredient-. rug/Tablet Part II - Granulatincr Agent Starch, NF 26.7 mg Purified Water, USP q.s 5 Part III - Excipients.
Sodium Lauryl Sulfate,, NF 0.77 mg Magnesium Stearate, NF ■ 2.05 nig 10 Total ■ 422.65' rhg B. Sustained Release Laver Part I~ Active and Ercinients 15 Acetaminophen,, USP 333.33 mg Hydroxyethyl Cellulose, NF 11.0 mg (Natrosol* 250L) Microcrystalline Cellulose, NF 11.0 mg (Avicel® PH 101) 20 Part II - Granulating Agent Povidone, USP 11.0 mg (Plasdone* K29/32) Purified Water,. USP q.s 25 Part III - Excioients Microcrystalline Cellulose, NF 15.4 mg (Avicel® PK 101) Pregelatinized Starch, NF 5.13 nig 30 (Starch 1500") Magnesium Stearate, NF 5.13 ma 35 Total Total Tablet Weight 391.94 mg 814.64 mg 9^ hi %r Example IV Acetaminophen Sustained Release Bi-layer Tablet Containing Less Than a Total of 650 mg Acetaminophen 5 This example illustrates a bi-layer tablet which is analogous to the tablet described in Example I, except all amounts of ingredients per tablet and final weight of the tablet are proportionally decreased. One practical decrease in the amount of acetaminophen would b® 150 mg 10 such that the total amount of acetaminophen in a tablet would be 500 mg. The working directions for the immediate release layer and the sustained release layer are analogous to the working directions described in Example I. Tablets can be compressed using capsule, oval, round 15 or other appropriately shaped tooling. For a tablet containing a total of 500 mg acetaminophen, the sustained release layer has a target weight of 293.89 mg and the immediate release layer has a target weight of 316.92 mg.
Ingredient 2 0 A. Immediate Release Laver ma/Tablet Part I - Active and Excioients Acetaminophen, USP Powdered Cellulose, NF 250 mg 32.5 mg 12.3 mg 25 Pregelatinized Starch, NF Part II ~ Granulating Agent Starch, NF Purified Water, USP 20.0 mg q.S. 30 Part III - Excipients Sodium LaurylSulfate, NF Magnesium Stearate, NF 0.58 mg 1.54 ma 35 Total 316.92 mg r* I na ted lent fng/Tgb-lSX.
B. Sustained Release Layer 5 Part I - Active and Ercioients Acetaminophen, USP 250.0 mg Hydroxyethyl Cellulose, NF 8.23 mg (Natrosol* 250L) Microcrystalline Cellulose,. NF 8.23 mg 10 ' ' (Avicel* PH 101) 8.23 mg q.s.
« Part III - Excipients Microcrystalline Cellulose, NF 11.5 mg (Avicel* PH 101) 20 Pregelatinized Starch, NF 3.85 mg (Starch 1500s) Magnesium Stearate, NF — Part II - Granulating Agent Povidone, USP (Plasdone* K29/32) 15 Purified Water, USP 25 Total Total Tablet Weight 293.89 rag 610.81 mg y / £ 35
Claims (1)
1. CLAIMS: 1. A process of preparing an acetaminophen-sustained release shaped and compressed tablet characterised by a slow 5 release of the acetaminophen upon administration comprising the following steps: A) forming a granulating agent by dissolving 5-25 parts by weight of polyvinylpyrrolidone (Povidone) in water 10 or in an alcohol-water mixture; B) blending together the following parts by weight of the total composition of ingredients with sufficient acetaminophen so that the acetaminophen comprises 68 to 94 percent by weight of the total' composition in 15 dry powder form: Ingredient Parts bv Weight, ■ hydroxyethyl cellulose 5-25 wicking agent 5-25 20 C) adding the granulating agent, from Step k to the blended powders from Step B, and mixing in a high shear granulator to form a wet ..granulation ; D) drying the wet granulation of Step C; 25 E) milling the dried granulation from Step D| F) thoroughly blending the milled dried granulation, from Step S with the following parts by weight of ingredients, in dry powder form: 30 Ingredient Parts bv Weight erosion promoter 1-15 wicking agent 5-45 lubricant 0-10 glidant 0-5 G) compressing the final granulation from Step F into a tablet or tablet layer. 28 2. A process according to claim 1 wherein: in Step A, when any alcohol is used, it is ethyl alcohol, dehydrated ethylalcohol, methyl alcohol or isopropyl alcohol, and is used in a quantity equal to or less than the 5 water in the alcohol-water mixture; in Step B the wicking agent used is microcrystalline cellulose or powdered cellulose; in Step F the erosion, promoter used is 2-15 parts by weight of pregelatinized starch, starch NF or rice starch, or is 1-10 10 parts by . weight ; of sodium starch glycolate, croscarmellose sodium or crospovidone; the lubrican- used is magnesium stearate or stearic acid;- and, the glidant used is colloidal silicon dioxide or fumed silicon dioxide- 15 3. A process according to claim 1 or claim 2 wherein,: in Step A water is used; in Step B the wicking agent used is microcrystalline cellulose; in Step F the erosion promoter used is pregelatinized 2 0 starch; and the lubricant used is magnesium stearate. 4. A process according to any one of claims I to 3 wherein the specific ingredients and amounts used are: 25 Steo Incredient Parts bv Weiaht A water q.s. Povidone ' iq.7 B Acetaminophen 325.0 Hydroxyethyl Cellulose 10.7 30 P Pregelatinized Starchi 5.0 Microcrystalline Cellulose 15.0 Magnesium stearate 5.0 5. The process of any one of claims 1 to 4 wherein the 35 Parts by Height shown refer to milligrams per tablet™ 6. A shaped and compressed sustained release therapeutic composition comprising acetaminophen, a granulating agent 29 and excipients combined into a matrix, characterised by a slow release of the acetaminophen upon administration, wherein the granulating agent and excipients include hydroxyethyl cellulose, povidone, a wicking agent and an 5 erosion promoter, and wherein the total amount of granulating agent and excipients is effective to bind the acetaminophen in a sustained release solid matrix but is less than 32 percent of the weight of said shaped and compressed composition , the composition being made by the 10 process according-to claim 1. 7. h composition according to claim 6 'wherein the wicking agent is microcrystalline cellulose and the erosion promoter is pregelatinized starch- 15 fi. A composition according to claim 6 or claim 7 wherein the total amount of granulating agent and excipients is greater than 6 but less than 15 percent of the total weight of said shaped and compressed composition, 20 9» A composition which is a shaped and compressed acetaminophen sustained release tablet made by wet granulating a sufficient amount of acetaminophen to comprise from 68 to 94 weight percent of the total composition with the Excipients of Part I and 25 the Granulating Agent of Part II, drying and milling the resultant . granulations, and then blending with the Excipients of Part III and compressing into a tablet,, - wherein the ingredients of Parts I, II and III comprise the following" 30 Ingredient Parts bv Height Part.I Excipients hydroxyethyl cellulose 5-25 microcrystalline cellulose 5-25 3 5 Part II Granulating Agent povidone 5-25 water or alcohol-water q.s. Excioients pregelatinized starch 2- •15 microcrystalline cellulose 5- ■45 magnesium stearate 0- 10 colloidal silicon dioxide 0- 5 10. A tablet according to claim 9 wherein the Parts by Weight refer to milligrams per tablet, and wherein the ingredients are present, either in the weights indicated or 10 in such weights'multiplied by a:h appropriate fraction, ■ • 11. A process of preparing an acetaminophen sustained release bi-layer. tablet comprising a first layer of immediate release and a second layer of sustained slow 15 release of acetaminophen according to the steps of: I) preparing an immediate release layer comprising acetaminophen and pharmaceutical^ acceptable excipients; XI) preparing a sustained release layer comprising 20 acetaminophen as the active ingredient according to Steps A to F of claim l; and III) combining and compressing the immediate release layer of Step I with the sustained release layer of Step II into a bi-lavered tablet. 25 12. A process according to claim 11 wherein Steps Ae B and F are as defined in claim 2. 13. A process according to claim 12 wherein: 3 0 in Step B the wicking agent is microcrystalline cellulose; in Step C the wet granulation is formed by mixing in a high shear granulator; and in Step F the erosion promoter is pregelatinized 35 starch, the lubricant is magnesium stearate^ and the glidant is colloidal silicon dioxide. 0 x 14. A process according to any one of claims 11 to 13 wherein the immediate release layer comprises a composition of the following ingredients; acetaminophen; powdered cellulose? pregelatinized 5 starch," sodium lauryl sulphate; magnesium stearate; and a granulating agent. 15. h shaped and compressed bi-layer therapeutic composition comprising acetaminophen in a first immediate 10 release layer and in a second sustained release layer,, wherein the immediate release layer comprises acetaminophen and pharmaceutically acceptable excipients and the sustained release layer comprises the composition according to claim 6. 15 IS. A therapeutic composition according to claim 15 wherein the immediate release layer comprises acetaminophen; powdered cellulose; pregelatinized starch; sodium lauryl sulphate; magnesium stearate; and a granulating agent. 20 17. A therapeutic composition according to claim 15 or claim 16 wherein, the amount of granulating agent and excipients is greater than 6 percent but less than A 5 percent of the total weight or the sustained 25 release layer of said shaped and compressed bi-layer composition. 18. A shaped and compressed bi-layered immediate release layer and sustained release layer acetaminophen tablet made 3 0 by combining an immediate release layer comprising acetaminophen and pharmaceutical^ acceptable excipients with a composition according to claim 9.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/078,138 US4820522A (en) | 1987-07-27 | 1987-07-27 | Oral sustained release acetaminophen formulation and process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE882286L true IE882286L (en) | 1989-01-27 |
| IE62831B1 IE62831B1 (en) | 1995-03-08 |
Family
ID=22142148
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE228688A IE62831B1 (en) | 1987-07-27 | 1988-07-26 | Orally sustained-release acetaminophen formulation and process to obtain it |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US4820522A (en) |
| EP (1) | EP0305051B1 (en) |
| JP (1) | JP2720932B2 (en) |
| KR (1) | KR960005706B1 (en) |
| AU (1) | AU611704B2 (en) |
| CA (1) | CA1315202C (en) |
| DE (1) | DE3880762T2 (en) |
| ES (1) | ES2054813T3 (en) |
| GR (1) | GR1000254B (en) |
| HK (1) | HK87893A (en) |
| IE (1) | IE62831B1 (en) |
| IN (1) | IN166560B (en) |
| NZ (1) | NZ225402A (en) |
| PH (1) | PH25376A (en) |
| PT (1) | PT88099B (en) |
| ZA (1) | ZA885460B (en) |
Families Citing this family (89)
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| JP5827952B2 (en) | 2009-10-09 | 2015-12-02 | ユンジン・ファーム・カンパニー・リミテッドＹｕｎｇｊｉｎ Ｐｈａｒｍ． Ｃｏ． Ｌｔｄ． | Pharmaceutical composition having both rapid action and durability |
| SG194605A1 (en) * | 2011-05-06 | 2013-12-30 | Glaxosmithkline Llc | Sustained release paracetamol formulations |
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| CA2936741C (en) | 2014-10-31 | 2018-11-06 | Purdue Pharma | Methods and compositions particularly for treatment of attention deficit disorder |
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| GB1390032A (en) * | 1971-08-27 | 1975-04-09 | Sterling Winthrop Group Ltd | Pharmaceutical compositions |
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-
1987
- 1987-07-27 US US07/078,138 patent/US4820522A/en not_active Expired - Lifetime
-
1988
- 1988-06-20 IN IN503/CAL/88A patent/IN166560B/en unknown
- 1988-07-13 NZ NZ225402A patent/NZ225402A/en unknown
- 1988-07-25 KR KR1019880009313A patent/KR960005706B1/en not_active IP Right Cessation
- 1988-07-25 CA CA000572939A patent/CA1315202C/en not_active Expired - Lifetime
- 1988-07-25 AU AU20012/88A patent/AU611704B2/en not_active Ceased
- 1988-07-26 EP EP88306879A patent/EP0305051B1/en not_active Expired - Lifetime
- 1988-07-26 DE DE8888306879T patent/DE3880762T2/en not_active Expired - Fee Related
- 1988-07-26 JP JP63184787A patent/JP2720932B2/en not_active Expired - Lifetime
- 1988-07-26 GR GR880100491A patent/GR1000254B/en unknown
- 1988-07-26 ES ES88306879T patent/ES2054813T3/en not_active Expired - Lifetime
- 1988-07-26 PT PT88099A patent/PT88099B/en not_active IP Right Cessation
- 1988-07-26 ZA ZA885460A patent/ZA885460B/en unknown
- 1988-07-26 IE IE228688A patent/IE62831B1/en not_active IP Right Cessation
-
1989
- 1989-07-25 PH PH37269A patent/PH25376A/en unknown
-
1993
- 1993-08-26 HK HK878/93A patent/HK87893A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CA1315202C (en) | 1993-03-30 |
| IE62831B1 (en) | 1995-03-08 |
| AU611704B2 (en) | 1991-06-20 |
| JPS6440424A (en) | 1989-02-10 |
| JP2720932B2 (en) | 1998-03-04 |
| AU2001288A (en) | 1989-04-20 |
| EP0305051B1 (en) | 1993-05-05 |
| KR960005706B1 (en) | 1996-05-01 |
| NZ225402A (en) | 1990-06-26 |
| US4820522A (en) | 1989-04-11 |
| PT88099A (en) | 1989-06-30 |
| DE3880762T2 (en) | 1993-09-23 |
| IN166560B (en) | 1990-06-09 |
| DE3880762D1 (en) | 1993-06-09 |
| PT88099B (en) | 1995-03-01 |
| KR890001526A (en) | 1989-03-27 |
| PH25376A (en) | 1991-06-03 |
| ES2054813T3 (en) | 1994-08-16 |
| ZA885460B (en) | 1990-03-28 |
| GR880100491A (en) | 1989-04-12 |
| HK87893A (en) | 1993-09-03 |
| EP0305051A1 (en) | 1989-03-01 |
| GR1000254B (en) | 1992-05-12 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |